The role of the kynurenine pathway in conditioned place aversion induced by synthetic cannabinoid CP-55940

The therapeutic potential of cannabinoids is increasingly recognized; however, their use is often associated with adverse effects, such as conditioned place aversion (CPA). The molecular mechanisms underlying CPA remain poorly understood, particularly the role of the kynurenine pathway (KP) and its interaction with cannabinoid receptors. This study aimed to elucidate these mechanisms, focusing on the synthetic. We employed a mouse conditioned place preference behavioral model to assess CPA following the administration of CP-55940 at a dosage of 1 mg/kg via intraperitoneal injection. We conducted a comprehensive analysis of key metabolites in the kynurenine pathway, specifically measuring levels of kynurenic acid (KYNA) in the hippocampus, while also monitoring quinolinic acid levels for comparison. Additionally, we utilized pharmacological inhibition of KATII with PF-04859989 to further explore KYNA’s role in mediating CPA. Our findings revealed significant increases in tryptophan, kynurenine, and KYNA levels in the hippocampus following administration of CP-55940, whereas quinolinic acid levels remained unchanged. Notably, pharmacological inhibition of KATII effectively reduced CPA, thereby affirming the critical role of KYNA in the aversive response. Furthermore, we observed that KYNA downregulated CB1 receptor (CB1R) expression, which was restored upon inhibition of KYNA synthesis. Additionally, G protein-coupled receptor 35 (GPR35) expression was significantly reduced in the CPA model, and its levels were positively correlated with KYNA, suggesting intricate molecular interactions. This study elucidates the complex interplay between KYNA, CB1R, and GPR35 in the context of cannabinoid-induced CPA, highlighting the pivotal role of the TRP–KYN pathway in mediating adverse behavioral effects associated with cannabinoids. These findings open avenues for the development of therapeutic targets aimed at mitigating such effects. Future research should focus on validating these results through gene knockout models and further exploring the clinical implications of KYNA modulation in cannabinoid pharmacology and neuropsychiatric disorders.